Skip to main content

Advertisement

SpringerLink
Log in

New Insights in the Treatment Strategy for Pulmonary Arterial Hypertension

  • Review
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Introduction

Recent advances in our understanding of the pathophysiological and molecular mechanisms involved in pulmonary arterial hypertension have led to the development of novel and rational pharmacological therapies. In addition to conventional therapy (i.e., supplemental oxygen and calcium channel blockers), prostacyclin or endothelin receptor antagonists have been recommended as a first-line therapy for pulmonary arterial hypertension. However, these treatments have potential limitations with regard to their long-term efficacy and improvement in survival. Furthermore, intravenous prostacyclin (epoprostenol) therapy, which is recommended by most experts for patients with New York Heart Association (NYHA) functional class IV, is complicated, uncomfortable for patients, and expensive because of the cumbersome administration system. Considering these circumstances, it is necessary to develop additional novel therapeutic approaches that target the various components of this multifactorial disease.

Case report

In this short review, we present an overview of the current treatment options for pulmonary arterial hypertension and describe a case report with primary pulmonary hypertension. A male patient with NYHA functional class IV and showing no response to calcium channel blockers and prostacyclin exhibited significantly improved exercise tolerance and hemodynamics and long-term survival for more than 2.5 years after receiving an oral combination therapy of a phosphodiesterase type 5 inhibitor (sildenafil), phosphodiesterase type 3 inhibitor (pimobendan), and nicorandil.

Future perspective

We also discuss the background and plausible potential mechanisms involved in this case, as well as future perspectives in the treatment of pulmonary arterial hypertension.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rubin LJ. Pathology and pathophysiology of primary pulmonary hypertension. Am J Cardiol 1995;75:51A–4.

    Article  CAS  PubMed  Google Scholar 

  2. Archer S, Rich S. Primary pulmonary hypertension: a vascular biology and translational research “work in progress”. Circulation 2000;102:2781–91.

    CAS  PubMed  Google Scholar 

  3. Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet 2003;361:1533–44.

    Article  PubMed  Google Scholar 

  4. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336:111–7.

    Article  CAS  PubMed  Google Scholar 

  5. Rabinovitch M. Pulmonary hypertension: updating a mysterious disease. Cardiovasc Res 1997;34:268–72.

    Article  CAS  PubMed  Google Scholar 

  6. Farber HW, Loscalzo JL. Pulmonary arterial hypertension. N Engl J Med 2004;351:1655–65.

    Article  CAS  PubMed  Google Scholar 

  7. Partovian C, Adnot S, Raffestin B, Louzier V, Levame M, Mavier IM, et al. Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. Am J Respir Cell Mol Biol 2000;23:762–71.

    CAS  PubMed  Google Scholar 

  8. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:214–21.

    Article  CAS  PubMed  Google Scholar 

  9. Giaid A, Yanagisawa M, Langleben D, Michel R, Levy H, Shennib S, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732–39.

    Article  CAS  PubMed  Google Scholar 

  10. Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992;327:70–5.

    Article  CAS  PubMed  Google Scholar 

  11. Rubin LJ. Therapy of pulmonary hypertension: the evolution from vasodilators to antiproliferative agents. Am J Respir Crit Care Med 2002;166:1308–9.

    Article  PubMed  Google Scholar 

  12. Barst RJ, Rubin LJ, Long WA, McGoon M, Rich S, Badesch D, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296–302.

    Article  CAS  PubMed  Google Scholar 

  13. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106:1477–82.

    Article  CAS  PubMed  Google Scholar 

  14. Rubin LJ, Badesch DB, Barst LJ, Galie N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896–903.

    Article  CAS  PubMed  Google Scholar 

  15. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425–36.

    Article  CAS  PubMed  Google Scholar 

  16. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76–81.

    Article  CAS  PubMed  Google Scholar 

  17. Sitbon O, Humbert M, Jagot JL, Taravella O, Fartoukh M, Parent F, et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J 1998;12:265–70.

    Article  CAS  PubMed  Google Scholar 

  18. Moncada S, Gryglewsli R, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 1976;263:663–5.

    Article  CAS  PubMed  Google Scholar 

  19. Clapp LH, Finney P, Turcato S, Tran S, Rubin LJ, Tinker A. Differential effects of stable prostacyclin analogues on smooth muscle proliferation and cyclic AMP generation in human pulmonary artery. Am J Respir Cell Mol Biol 2002;26:194–201.

    CAS  PubMed  Google Scholar 

  20. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780–8.

    Article  CAS  PubMed  Google Scholar 

  21. Humbert M, Sanchez O, Fartoukh M, Jagot JL, Le Gall C, Sitbon O, et al. Short-term and long-term epoprostenol (prostacyclin) therapy in pulmonary hypertension secondary to connective tissue diseases: results of a pilot study. Eur Respir J 1999;13:1351–6.

    Article  CAS  PubMed  Google Scholar 

  22. Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge R, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind randomized controlled trial. Am J Respir Crit Care Med 2002;165:800–4.

    PubMed  Google Scholar 

  23. Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind placebo-controlled trial. J Am Coll Cardiol 2002;39:1496–1502.

    Article  CAS  PubMed  Google Scholar 

  24. Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije MD, Rubin L, et al. Inhaled iloprost in severe pulmonary hypertension. N Engl J Med 2002;347:322–7.

    Article  CAS  PubMed  Google Scholar 

  25. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411–5.

    Article  CAS  PubMed  Google Scholar 

  26. Fagan KA, McMurtry IF, Rodman DM. Role of endothelin-1 in lung disease. Respir Res 2001;2:90–101.

    Article  CAS  PubMed  Google Scholar 

  27. Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119–23.

    Article  CAS  PubMed  Google Scholar 

  28. Sitbon O, Badesch DB, Channick RN, Frost A, Robbins IM, Simonneau G, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest 2003;124:247–54.

    Article  CAS  PubMed  Google Scholar 

  29. Mehta S. Sildenafil for pulmonary arterial hypertension: exciting, but protection required. Chest 2003;123:989–92.

    Article  PubMed  Google Scholar 

  30. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 1991;338:1173–4.

    Article  CAS  PubMed  Google Scholar 

  31. Hasuda T, Satoh T, Shimouchi A, Sakamaki F, Kyotani S, Matsumoto T, et al. Improvement in exercise capacity with nitric oxide inhalation in patients with precapillary pulmonary hypertension. Circulation 2000;101:2066–70.

    CAS  PubMed  Google Scholar 

  32. Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 2001;104:1218–22.

    CAS  PubMed  Google Scholar 

  33. Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002;360:895–900.

    Article  CAS  PubMed  Google Scholar 

  34. Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Kreckel A, et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 2003;42:158–64.

    Article  CAS  PubMed  Google Scholar 

  35. Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. N Engl J Med 2000;343:1342.

    Article  CAS  PubMed  Google Scholar 

  36. Stiebellehner L, Petkov V, Vonbank K, Funk G, Schenk P, Ziesche R, et al. Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension. Chest 2003;123:1293–5.

    Article  PubMed  Google Scholar 

  37. Michelakis ED, Tymchak W, Noga M, Webster L, Wu X-C, Lien D, et al. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 2003;108:2066–9.

    Article  CAS  PubMed  Google Scholar 

  38. Sastry BK, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004;43:1149–53.

    Article  CAS  PubMed  Google Scholar 

  39. Galie N, Ghofrani HA, Torbicki A, Barst R, Rubin L, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148–57.

    Article  CAS  PubMed  Google Scholar 

  40. Murray F, MacLean MR, Pyne NJ. Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension. Br J Pharmacol 2002;37:1187–94.

    Article  CAS  PubMed  Google Scholar 

  41. Tasatargil A, Sadan G, Ozdem SS. The effects of selective phosphodiesterase III and V inhibitors on adrenergic and non-adrenergic, non-cholinergic relaxation responses of guinea-pig pulmonary arteries. Auton Autacoid Pharmacol 2003;23:117–24.

    Article  CAS  PubMed  Google Scholar 

  42. Effects of Pimobendan on Chronic Heart Failure Study (EPOCH Study). Effects of pimobendan on adverse cardiac events and physical activities in patients with mild to moderate chronic heart failure: the effects of pimobendan on chronic heart failure study (EPOCH study). Circ J 2002;66:149–57.

    Article  Google Scholar 

  43. Taira N. Nicorandil as a hybrid between nitrates and potassium channel activators. Am J Cardiol 1989;63:18J–24J.

    Article  CAS  PubMed  Google Scholar 

  44. Hongo M, Takenaka H, Uchikawa S, Nakatsuka T, Watanabe N, Sekiguchi M. Coronary microvascular response to intracoronary administration of nicorandil. Am J Cardiol 1995;75:246–50.

    Article  CAS  PubMed  Google Scholar 

  45. Akai K, Wang Y, Sato K, Sekiguchi N, Sugimura A, Kumagai T, et al. Vasodilatory effect of nicorandil on coronary arterial microvessels: its dependency on vessel size and the involvement of the ATP-sensitive potassium channels. J Cardiovasc Pharmacol 1995;26:541–7.

    Article  CAS  PubMed  Google Scholar 

  46. Yanagisawa T, Yamagishi T, Okada Y. Hyperpolarization induced by K+ channel openers inhibits Ca2+ influx and Ca2+ release in coronary artery. Cardiovasc Drugs Ther 1993;7:565–74.

    Article  PubMed  Google Scholar 

  47. Schultz JE, Yao Z, Cavero I, Gross GJ. Glibenclamide-induced blockade of ischemic preconditioning is time dependent in intact rat heart. Am J Physiol 1997;272:H2607–15.

    CAS  PubMed  Google Scholar 

  48. Sato T, Sasaki N, O’Rourke B, Marban E. Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATP-dependent potassium channels. J Am Coll Cardiol 2000;35:514–8.

    Article  CAS  PubMed  Google Scholar 

  49. Hongo M, Mawatari E, Sakai A, Zonghai R, Koizumi T, Terasawa F, et al. Effects of nicorandil on monocrotaline-induced pulmonary arterial hypertension in rats. J Cardiovasc Pharmacol 2005;46:452–8.

    Article  CAS  PubMed  Google Scholar 

  50. Hutter AM Jr. Role of the cardiologist: clinical aspects of managing erectile dysfunction. Clin Cardiol 2004;27:I3–7.

    PubMed  Google Scholar 

  51. Kamijo T, Kamei K, Sugo I, Kamiyama T, Sudo H, Ohba Y. Hemodynamic and hormonal responses to nicorandil in a canine model of acute ischemic heart failure: a comparison with cromakalim and nitroglycerin. J Cardiovasc Pharmacol 1999;33:93–101.

    Article  CAS  PubMed  Google Scholar 

  52. Humbert M, Sitbon O, Simonneau G. Novel therapeutic perspectives in pulmonary arterial hypertension. Eur Respir J 2003;22:193–4.

    Article  CAS  PubMed  Google Scholar 

  53. Hoeper MM, Taha N, Bekjarova A, Gatzke R, Spiekerkoetter E. Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids. Eur Respir J 2003;22:330–4.

    Article  CAS  PubMed  Google Scholar 

  54. Bhatia S, Frantz RP, Severson CJ, Durst LA, McGoon MD. Immediate and long-term hemodynamic and clinical effects of sildenafil in patients with pulmonary arterial hypertension receiving vasodilator therapy. Mayo Clin Proc 2003;78:1207–13.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Makoto Sahara, Toshiyuki Takahashi, Yasushi Imai, Toshiaki Nakajima, Atsushi Yao, Toshihiro Morita, Yasunobu Hirata & Ryozo Nagai

Authors
  1. Makoto Sahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshiyuki Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasushi Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toshiaki Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Atsushi Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Toshihiro Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasunobu Hirata
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ryozo Nagai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Makoto Sahara.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sahara, M., Takahashi, T., Imai, Y. et al. New Insights in the Treatment Strategy for Pulmonary Arterial Hypertension. Cardiovasc Drugs Ther 20, 377–386 (2006). https://doi.org/10.1007/s10557-006-0498-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-006-0498-3

Key words

Search

Navigation